Benzodiazepine withdrawal syndrome


Benzodiazepine withdrawal syndrome

] Various studies have shown between 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms. [cite book |last= Ashton |first= CH |editor= A Baum, S. Newman, J. Weinman, R. West, C. McManus |title= Cambridge Handbook of Psychology & Medicine |accessdate= 03 |accessyear= 2007 |accessmonth= 07 |year= 1997 publisher= Cambridge University Press |location= England |pages= 376-80 |chapter= Benzodiazepine Dependency |chapterurl= http://www.benzo.org.uk/bzdep.htm]

Benzodiazepine dependence is a frequent complication when they are prescribed for or taken for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis, and epileptic seizures. The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, and use of potent short-acting benzodiazepines among those with certain pre-existing personality characteristics such as dependent personalities, and those prone to drug abuse. [cite journal |author=Marriott S, Tyrer P. |title=Benzodiazepine dependence. Avoidance and withdrawal |journal=Drug safety : an international journal of medical toxicology and drug experience. |volume=9 |issue=2 |pages=93–103 |month=Aug |year=1993 |pmid=8104417]

Previously, physical dependence on benzodiazepines was largely thought to occur only in people on high-therapeutic-dose ranges, and low- or normal-dose dependence was not suspected until the 1970s; and it wasn't until the early 1980s that it was confirmed. [cite journal |author= Lader M. |coauthors= |title=History of benzodiazepine dependence |journal=Journal of substance abuse treatment. |volume=8 |issue=1-2 |pages=53–9 |month= |year=1991 |pmid=1675692|doi=10.1016/0740-5472(91)90027-8] However, low-dose dependence is now a recognized clinical disadvantage of benzodiazepines, and severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction. [cite journal |author= Lader M. |coauthors= |title=Long-term anxiolytic therapy: the issue of drug withdrawal |journal=The Journal of clinical psychiatry. |volume=48 |issue= |pages=12–6 |month=Dec |year=1987 |pmid=2891684] [cite journal |author= Miura S |coauthors=Murasaki M |title=The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives) |journal=Progress in neuro-psychopharmacology & biological psychiatry. |volume=16 |issue=6 |pages=833–45 |month=Mar |year=1992 |pmid=1355301 |doi=10.1016/0278-5846(92)90103-L] Low dose dependence has now been clearly demonstrated in both animal studies and human studies. [cite journal |author= Lucki I |coauthors=Kucharik RF. |title=Increased sensitivity to benzodiazepine antagonists in rats following chronic treatment with a low dose of diazepam |journal=Psychopharmacology. |volume=102 |issue=3 |pages=350–6 |month= |year=1990 |pmid=1979180 |doi=10.1007/BF02244103] [cite journal |author= Rickels K |coauthors=Case WG, Schweizer EE, Swenson C, Fridman RB. |title=Low-dose dependence in chronic benzodiazepine users: a preliminary report on 119 patients |journal=Psychopharmacology bulletin. |volume=22 |issue=2 |pages=407–15 |month= |year=1986 |pmid=2877472]

In an animal study of four baboons on low-dose benzodiazepine treatment, three out of the four baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment. Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms because low-dose benzodiazepine therapy was continued over a period of 6–10 months, suggesting rapid onset of dependence with benzodiazepines and suggesting that physical dependence was complete after two weeks of chronic, low-dose benzodiazepine treatment. [cite journal |author=Kaminski BJ |coauthors=Sannerud CA, Weerts EM, Lamb RJ, Griffiths RR. |title=Physical dependence in baboons chronically treated with low and high doses of diazepam |journal=Behavioural pharmacology. |volume=14 |issue=4 |pages=331–42 |month=Jul |year=2003 |pmid=12838039] In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment, and withdrawal signs appeared after only three days after high-dose treatment, which demonstrated the extremely rapid development of tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines sensitized baboons to the development of physical dependence. [cite journal |author=Lukas SE |coauthors=Griffiths RR. |title=Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure |journal=European journal of pharmacology. |volume=100 |issue=2 |pages=163–71 |date=20 |month=Apr |year=1984 |pmid=6428921 |doi=10.1016/0014-2999(84)90218-8]

In humans, chronic, low-therapeutic-dose dependence was demonstrated in experimentally precipitated withdrawal using flumazenil to show physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic therapeutic low-dose subjects included increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch. Healthy control subjects who were not dependent on benzodiazepines exhibited no benzodiazepine withdrawal like effects or notable side effects. [cite journal |author=Mintzer MZ |coauthors=Stoller KB, Griffiths RR. |title=A controlled study of flumazenil-precipitated withdrawal in chronic, low-dose benzodiazepine users |volume=147 |issue=2 |pages=200–9 |month=Nov |year=1999 |pmid=10591888] In another study of 34 low-dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who received flumazenil whereas those receiving placebo experienced no withdrawal signs. It was also found that those dependent on low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to flumazenil precipitated benzodiazepine withdrawal. [cite journal |author=Bernik MA |coauthors=Gorenstein C, Vieira Filho AH. |title=Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users |journal=Journal of psychopharmacology (Oxford, England). |volume=12 |issue=2 |pages=146–50 |month= |year=1998 |pmid=9694026] It has been estimated that 30–45% of chronic low dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days to avoid dependence. [cite journal |author=Meier PJ |coauthors=Ziegler WH, Neftel K. |title= [Benzodiazepine--practice and problems of its use] |volume=118 |issue=11 |pages=381–92 |journal=Schweizerische medizinische Wochenschrift. |date=19 |month=Mar |year=1988 |pmid=3287602]

Some controversy remains, however, in the medical literature as to the exact nature of low-dose dependence and the difficulty in getting patients to discontinue their benzodiazepines, with some papers attributing the problem to predominantly drug-seeking behavior and drug craving, whereas other papers have found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users. [cite journal |author=Linden M |coauthors=Bär T, Geiselmann B. |title=Patient treatment insistence and medication craving in long-term low-dosage benzodiazepine prescriptions |volume=28 |issue=3 |pages=721–9 |journal=Psychological medicine. |date= |month=May |year=1998 |pmid=9626728 |doi=10.1017/S0033291798006734] [cite journal |author=Tyrer P. |coauthors= |title=Benzodiazepine dependence: a shadowy diagnosis |volume=59 |issue= |pages=107–19 |journal=Biochemical Society symposium. |date= |month= |year=1993 |pmid=7910738]

Cross tolerance

Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABAA receptor. "Cross tolerance" means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. Benzodiazepines are often used for this reason to detoxify alcohol-dependent patients, and can have life-saving properties in preventing and/or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremens. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics. [cite journal |author=Poulos CX |coauthors=Zack M. |title=Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers |journal=Behavioural pharmacology. |volume=15 |issue=7 |pages=503–12 |year=2004 |pmid=15472572 |doi=] However, alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in alcoholics.

There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates, and the nonbenzodiazepine drugs, corticosteroids which all act by enhancing the GABAA receptor's function via modulating the chloride ion channel function of the GABAA receptor. [cite journal |author=Khanna JM, Kalant H, Weiner J, Shah G |title=Rapid tolerance and cross-tolerance as predictors of chronic tolerance and cross-tolerance |journal=Pharmacol. Biochem. Behav. |volume=41 |issue=2 |pages=355–60 |year=1992 |pmid=1574525 |doi=] [ [http://www.who.int/medicines/areas/quality_safety/4.6ZopicloneCritReview.pdf World Health Organisation - Assessment of Zopiclone] ] [cite journal |author=Allan AM, Baier LD, Zhang X |title=Effects of lorazepam tolerance and withdrawal on GABAA receptor-operated chloride channels |journal=J. Pharmacol. Exp. Ther. |volume=261 |issue=2 |pages=395–402 |year=1992 |pmid=1374467 |doi=] [cite journal | author = Rooke KC. | coauthors = | year = 1976 | month = | title = The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice | journal = J Int Med Res | volume = 4 | issue = 5 | pages = 355–9 | pmid = 18375 ] [cite journal | journal = J Pharmacol Exp Ther | year = 2000 | month = Dec | volume = 295 | issue = 3 | pages = 1241–8 | title = Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself | author = Reddy DS | coauthors = Rogawski MA | pmid = 11082461 |url = http://jpet.aspetjournals.org/cgi/content/full/295/3/1241]

The Committee on the Review of Medicines

The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties and are therefore unsuitable treatments for conditions such as depression, tension headaches and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long term use of benzodiazepine hypnotics were beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep promoting properties within 3–14 days of continuous use and in the treatment of anxiety the committee found that there was little convincing evidence that benzodiazepines retained efficacy in the treatment of anxiety after 4 months continuous use due to the development of tolerance. The committee found that the regular use of benzodiazepines caused the development of dependence characterised by tolerance to the therapeutic effects of benzodiazepines and the development of the benzodiazepine withdrawal syndrome including symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours upon cessation of short acting; and 3–10 days after cessation of longer acting benzodiazepines. Withdrawal effects could occur after treatment lasting only 2 weeks at therapeutic dose levels however withdrawal effects tended to occur with habitual use beyond 2 weeks and were more likely the higher the dose. The withdrawal symptoms may appear to be similar to the original condition. The committee recommended that all benzodiazepine treatment be withdrawn gradually and recommended that benzodiazepine treatment be used only in carefully selected patients and that therapy be limited to short term use only. It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided. The central nervous system depressant effects of benzodiazepines may make driving or operating machinery dangerous and the elderly are more prone to these adverse effects. In the neonate high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia in the neonate and irregularities in the fetal heart. Benzodiazepines should be avoided in lactation. Withdrawal from benzodiazepines should be gradual as abrupt withdrawal from high doses of benzodiazepines may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhea. [cite journal | author = Committee on the Review of Medicines | year = 1980 | month = Mar | date = 29 | title = Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines | journal = Br Med J. | volume = 280 | issue = 6218 | pages = 910–2 | pmid = 7388368 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1601049&blobtype=pdf | format = pdf ]

Physiology of withdrawal

Withdrawal symptoms are a normal response in individuals who have chronically used benzodiazepines, and a side effect and result of drug tolerance. Symptoms typically emerge when dosage of the drug is reduced. GABA receptors are the most common receptor system in the central nervous system and use of benzodiazepines has a profound effect on almost every aspect of brain and body function, either directly or indirectly. Benzodiazepines cause a decrease in norepinephrine (noradrenaline), serotonin, acetylcholine and dopamine. These neurotransmitters are needed for normal memory, mood, muscle tone and coordination, emotional responses, endocrine gland secretions, heart rate and blood pressure control. With chronic benzodiazepine use, tolerance develops rapidly to most of its effects, so that when benzodiazepines are withdrawn, various neurotransmitter systems go into overdrive due to the lack of inhibitory GABA-ergic activity. Withdrawal symptoms then emerge as a result, and persist until the nervous system physically reverses the adaptions (physical dependence) which have occurred in the CNS.

Withdrawal symptoms typically consist of a mirror image of the drug's effects: sedative effects and suppression of REM and SWS stages of sleep can be replaced by insomnia, nightmares, and hypnogogic hallucinations; its antianxiety effects are replaced with anxiety and panic; muscle relaxant effects are replaced with muscular spasms or cramps; and anticonvulsant effects with seizures, especially in cold turkey or overly-rapid withdrawal.

Clinical trials have shown that benzodiazepines cause an extremely rapid development of tolerance and dependence. Withdrawal symptoms including rebound insomnia and rebound anxiety occurs after only 7 days administration of benzodiazepines. [cite journal| journal =Clin Pharmacol Ther| year =1982| month =Feb| volume =31| issue =2| pages =175–9| title =Lorazepam-efficacy, side effects, and rebound phenomena| author =Scharf MB| coauthors =Kales A, Bixler EO, Jacoby JA, Schweitzer PK| pmid =6120058] Another trial demonstrated rebound withdrawal effects after only 18 nights use of lorazepam as a benzodiazepine hypnotic. [cite journal| journal =Clin Pharmacol Ther | year =1983| month =Oct| volume =34| issue =4| pages =496–500| title =Effects of lorazepam and its withdrawal on sleep, performance, and subjective state| author =Walsh JK| coauthors =Schweitzer PK, Parwatikar S| pmid =6617072] Rebound day time anxiety, tension develops after only 7 days use of short acting benzodiazepine hypnotics. On withdrawal of benzodiazepines after 7 nights use, withdrawal related insomnia rebounds worse than baseline. [cite journal| journal =Pharmacology | year =1986| volume =32| issue =3| pages =121–30| title =Lorazepam: effects on sleep and withdrawal phenomena| author =Kales A| coauthors =Bixler EO, Soldatos CR, Jacoby JA, Kales JD| pmid =3960963| doi =10.1159/000138160] [cite journal| journal =Int Clin Psychopharmacol | year =1999 | month =Mar | volume =14| issue =2| pages =81–9| title =The use of lorazepam TID for chronic insomnia| author =Bonnet MH| coauthors =Arand DL| pmid =10220122| doi =10.1097/00004850-199903000-00004] Intermittent use of benzodiazepines even over a short period of time can cause rebound insomnia. [cite journal| journal =Clin Pharmacol Ther | year =1991 | month =Apr | volume =49| issue =4| pages =468–76| title =Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines| author =Kales A| coauthors =Manfredi RL, Vgontzas AN, Bixler EO, Vela-Bueno A, Fee EC| pmid =2015735 ] Day time withdrawal symptoms are commonly associated with triazolam. This is due to its very short half life. After only 10 nights of triazolam use patients report anxiety, become distressed, weight loss, panics and depression, felt unreal, and develop paranoia. These reactions occurred more commonly with triazolam than lormetazepam which has an intermediate half life. Thus the more short acting a benzodiazepine hypnotic the more severe the day time withdrawal symptoms. [cite journal| journal =Pharmacopsychiatry | year =1989 | month =May | volume =22| issue =3| pages =115–9| title =Can a rapidly-eliminated hypnotic cause daytime anxiety? | author =Adam K | coauthors =Oswald I| pmid =2748714]

Patients consuming who are physically dependent on short acting anxiolytic benzodiazepines may experience what is known as interdose withdrawal. Interdose withdrawal are withdrawal symptoms which occur between doses when the previous dose wears off. This can lead to withdrawal symptoms such as rebound anxiety between doses and craving for the next dose of short acting benzodiazepine. [cite journal| journal =J Clin Psychopharmacol | year =1987 | month =Jun | volume =7| issue =3| pages =175–8| title =The alprazolam to clonazepam switch for the treatment of panic disorder | author =Herman JB | coauthors =Rosenbaum JF, Brotman AW| pmid =3597803| doi =10.1097/00004714-198706000-00012] [cite journal| journal =J Clin Psychiatry | year =1987 | month =Oct | volume =48 Suppl | pages =22–8| title =Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines | author =Herman JB | coauthors =Brotman AW, Rosenbaum JF | pmid =2889722]

Withdrawal symptoms

Some of the withdrawal symptoms are identical to the symptoms for which the medication was originally prescribed. The ability to determine the difference between relapse and rebound is very important during the withdrawal phase and can often lead to a misdiagnosis. For this reason, many experts agree that after withdrawal from long term or even fairly short term use of benzodiazepine drugs, at least six months should have elapsed prior to re-evaluating the symptoms and updating a diagnosis.

Common symptoms include:

* Electric shock sensationscite journal |journal=Br J Clin Pharmacol |year=1981 |volume=11 |issue=Suppl 1 |pages=5S–9S |title=The use of benzodiazepines in clinical practice |author=Shader RI |coauthors=Greenblatt DJ |pmid=6133535 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1401641&blobtype=pdf]
* Muscular spasms, cramps or fasciculationsKliniska Färdigheter: Informationsutbytet Mellan Patient Och Läkare, LINDGREN, STEFAN, ISBN 91-44-37271-X (Swedish)]
* Insomniacite journal |journal=Nouv Presse Med |year=1980 |month=Jun |date=28 |volume=9 |issue=28 |pages=1941–5 |title= [Benzodiazepine physical dependence. 6 cases (author's transl)] |author=Bismuth C |coauthors=Le Bellec M, Dally S, Lagier G |pmid=6106922 ]
* Headachecite journal |journal=Addiction |year=1994 |month=Nov |volume=89 |issue=11 |pages=1455–9 |title=The benzodiazepine withdrawal syndrome |author=Pétursson H |pmid=7841856 |doi=10.1111/j.1360-0443.1994.tb03743.x ]
* Rebound REM sleep [cite journal |journal=Prim Care Companion J Clin Psychiatry |year=2001 |month=Jun |volume=3 |issue=3 |pages=118–125 |title=Medications for the Treatment of Sleep Disorders: An Overview |author=Pagel JF |coauthors=Parnes BL |pmid=15014609 |url=http://www.psychiatrist.com/pcc/pccpdf/v03n03/v03n0303.pdf |format=PDF ]
* Hyperosmiacite journal |journal=Encephale |year=1994 |month=Mar-Apr |volume=20 |issue=2 |pages=147–57 |title= [Dependence on benzodiazepines. Clinical and biological aspects] |author=Pelissolo A |coauthors=Bisserbe JC |pmid=7914165 ]
* Metallic tastecite journal |journal=Encephale |year=1994 |month=Mar-Apr |volume=20 |issue=2 |pages=147–57 |title= [Dependence on benzodiazepines. Clinical and biological aspects] |author=Pelissolo A |coauthors=Bisserbe JC |pmid=7914165 ]
* Photophobiacite journal |journal=Encephale |year=1994 |month=Mar-Apr |volume=20 |issue=2 |pages=147–57 |title= [Dependence on benzodiazepines. Clinical and biological aspects] |author=Pelissolo A |coauthors=Bisserbe JC |pmid=7914165 ]
* Paranoiacite journal |journal=Encephale |year=1994 |month=Mar-Apr |volume=20 |issue=2 |pages=147–57 |title= [Dependence on benzodiazepines. Clinical and biological aspects] |author=Pelissolo A |coauthors=Bisserbe JC |pmid=7914165 ]
* Hypnagogia-hallucinationscite web| author= Professor Heather Ashton| year= 2004| url= http://www.bcnc.org.uk/protracted.html| title= Protracted Withdrawal Symptoms From Benzodiazepines | publisher= Comprehensive Handbook of Drug & Alcohol Addiction]
* Nausea and vomitingcite journal |journal=Nouv Presse Med |year=1980 |month=Jun |date=28 |volume=9 |issue=28 |pages=1941–5 |title= [Benzodiazepine physical dependence. 6 cases (author's transl)] |author=Bismuth C |coauthors=Le Bellec M, Dally S, Lagier G |pmid=6106922 ]
* Nightmarescite journal |journal=Nouv Presse Med |year=1980 |month=Jun |date=28 |volume=9 |issue=28 |pages=1941–5 |title= [Benzodiazepine physical dependence. 6 cases (author's transl)] |author=Bismuth C |coauthors=Le Bellec M, Dally S, Lagier G |pmid=6106922 ]
* Anxiety, possible panic attackscite journal |journal=Addiction |year=1994 |month=Nov |volume=89 |issue=11 |pages=1455–9 |title=The benzodiazepine withdrawal syndrome |author=Pétursson H |pmid=7841856 |doi=10.1111/j.1360-0443.1994.tb03743.x ]
* Impaired concentrationcite journal |journal=Addiction |year=1994 |month=Nov |volume=89 |issue=11 |pages=1455–9 |title=The benzodiazepine withdrawal syndrome |author=Pétursson H |pmid=7841856 |doi=10.1111/j.1360-0443.1994.tb03743.x ]
* Elevation in blood pressure [cite journal |journal=Psychopharmacology (Berl) |year=2005 |month=Mar |volume=178 |issue=2-3 |pages=259–67 |title=Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure |author=Mintzer MZ |coauthors=Griffiths RR |pmid=15452683 |doi=10.1007/s00213-004-2009-1 ]
* Tachycardia [cite journal |journal=Ann Pharmacother |year=1993 |month=May |volume=27 |issue=5 |pages=579–81 |title=Benzodiazepine withdrawal reaction in two children following discontinuation of sedation with midazolam |author=van Engelen BG |coauthors=Gimbrere JS, Booy LH |pmid=8347907 ]
* Hypertension [cite journal |journal=Clin Toxicol (Phila) |year=2005 |volume=43 |issue=3 |pages=207–9 |title=Myocardial ischemia as a result of severe benzodiazepine and opioid withdrawal |author=Biswas AK |coauthors=Feldman BL, Davis DH, Zintz EA |pmid=15902797 ]
* Postural hypotensioncite journal |journal=Nouv Presse Med |year=1980 |month=Jun |date=28 |volume=9 |issue=28 |pages=1941–5 |title= [Benzodiazepine physical dependence. 6 cases (author's transl)] |author=Bismuth C |coauthors=Le Bellec M, Dally S, Lagier G |pmid=6106922 ]
* Depression (can be severe) [cite journal |journal=J Psychosom Res |year=1994 |volume=38 |issue=Suppl 1 |pages=113–23 discussion 118–23 |title=Anxiety or depression during withdrawal of hypnotic treatments |author=Lader M |pmid=7799243 |doi=10.1016/0022-3999(94)90142-2 ] , possible suicidal ideation
* Tremor [cite journal |journal=Can Med Assoc J |year=1982 |month=Dec |date=1 |volume=127 |issue=11 |pages=1093–6 |title=Diazepam withdrawal syndrome: its prolonged and changing nature |author=Mellor CS |coauthors= Jain VK |pmid=7139456 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1862031&blobtype=pdf |format=PDF ]
* Perspirationcite journal |journal=Addiction |year=1994 |month=Nov |volume=89 |issue=11 |pages=1455–9 |title=The benzodiazepine withdrawal syndrome |author=Pétursson H |pmid=7841856 |doi=10.1111/j.1360-0443.1994.tb03743.x ]
* Loss of appetite and weight loss [cite journal |journal=J Psychiatr Res |year=1993 |volume=27 |issue=Suppl 1 |pages=155–70 |title=Discontinuation reactions to alprazolam in panic disorder |author=Pecknold JC |pmid=8145176 |doi=10.1016/0022-3956(93)90025-W ]
* Dysphoria [cite journal |journal=Sleep |year=1982 |volume=5 |issue=4 |pages=350–60 |title=A clinical study of flurazepam |author=Mendelson WB |coauthors=Weingartner H, Greenblatt DJ, Garnett D, Gillin JC |pmid=6761826 ] [cite journal |journal=Pharmacopsychiatria |year=1983 | month = Jan |volume=16 |issue=1 |pages=1–8 |title=Withdrawal phenomena after long-term administration of benzodiazepines. A review of recent investigations |author=Schöpf J |pmid=6131447 ]
* Depersonalization [cite journal |author=Terao T |coauthors=Yoshimura R, Terao M, Abe K. |title=Depersonalization following nitrazepam withdrawal |journal=Biol Psychiatry |volume=31 |issue=2 |pages=212–3 |date=15 |month=Jan |year=1992 |pmid=1737083 |doi=10.1016/0006-3223(92)90209-I ] cite journal | journal = Br J Gen Pract | author = Neale G | coauthors = Smith AJ | year = 2007 | month = May | volume = 57 | issue = 538 | pages = 407–8 | title = Self-harm and suicide associated with benzodiazepine usage | pmid = 17504594 | publisher = pubmed central | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17504594 ]
* Derealisation (Feelings of unreality) [cite journal | journal = Psychopharmacology (Berl) | year = 1999 | month = Nov | volume = 147 | issue = 2 | pages = 200–9 | title = A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users | author = Mintzer MZ | coauthors = Stoller KB, Griffiths RR | pmid = 10591888 | doi = 10.1007/s002130051161 ]
* Tinnituscite journal | journal = BMJ | year = 1991 | month = Jun | date = 15 | volume = 302 | issue = 6790 | pages = 1465 | title = Benzodiazepines and tinnitus | author = Beeley L | pmid = 2070121 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1670117&blobtype=pdf | format = PDF ]
* Paraesthesiacite journal | journal = Br J Gen Pract | author = Neale G | coauthors = Smith AJ | year = 2007 | month = May | volume = 57 | issue = 538 | pages = 407–8 | title = Self-harm and suicide associated with benzodiazepine usage | pmid = 17504594 | publisher = pubmed central | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17504594 ] cite journal |journal=Encephale |year=1994 |month=Mar-Apr |volume=20 |issue=2 |pages=147–57 |title= [Dependence on benzodiazepines. Clinical and biological aspects] |author=Pelissolo A |coauthors=Bisserbe JC |pmid=7914165 ]
* Visual disturbancescite journal | journal = Br J Gen Pract | author = Neale G | coauthors = Smith AJ | year = 2007 | month = May | volume = 57 | issue = 538 | pages = 407–8 | title = Self-harm and suicide associated with benzodiazepine usage | pmid = 17504594 | publisher = pubmed central | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17504594 ]
* Gastrointestinal problems (Stomach and abdomen) [cite journal |author=Loeb P |coauthors= Adnet P, Boittiaux P, Forget AP, Mille FX. |title= [Benzodiazepine withdrawal presenting as pseudo-surgical abdominal pain] | doi = 10.1093/bja/aei040 |journal=Annales françaises d'anesthèsie et de rèanimation. |volume=16 |issue=5 |pages=521–2 |month= |year=1997 |pmid=9750606 ]

An abrupt or over-rapid discontinuation of benzodiazepines may result in a more serious and very unpleasant withdrawal syndrome that may additionally result in:

* Convulsions, which may result in death [cite journal |author=Metten P, Crabbe JC |title=Genetic determinants of severity of acute withdrawal from diazepam in mice: commonality with ethanol and pentobarbital |journal=Pharmacol. Biochem. Behav. |volume=63 |issue=3 |pages=473–9 |year=1999 |pmid=10418790 |doi=] [cite journal |author=Haque W, Watson DJ, Bryant SG |title=Death following suspected alprazolam withdrawal seizures: a case report |journal=Texas medicine |volume=86 |issue=1 |pages=44–7 |year=1990 |pmid=2300914 |doi=]
* Catatonia, which may result in death [cite journal |author=Rosebush PI |coauthors= Mazurek MF |title=Catatonia after benzodiazepine withdrawal |journal=Journal of clinical psychopharmacology |volume=16 |issue=4 |pages=315–9 |year=1996 |pmid=8835707 |doi=]
* Coma [cite journal |journal=Am J Psychiatry |year=1979 |month=Jan |volume=136 |issue=1 |pages=104–5 |title=Diazepam withdrawal syndrome: a case with psychosis, seizure, and coma |author=de Bard ML |pmid=103443 |doi=] (rare)
*Temporal lobe epilepsycite journal |journal=Br J Clin Pharmacol |year=1981 |volume=11 |issue=Suppl 1 |pages=5S–9S |title=The use of benzodiazepines in clinical practice |author=Shader RI |coauthors=Greenblatt DJ |pmid=6133535 |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1401641&blobtype=pdf]
*Suicide
* Attempted suicidecite journal | journal = Br J Gen Pract | author = Neale G | coauthors = Smith AJ | year = 2007 | month = May | volume = 57 | issue = 538 | pages = 407–8 | title = Self-harm and suicide associated with benzodiazepine usage | pmid = 17504594 | publisher = pubmed central | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17504594 ]
* Suicidal ideation [cite journal | journal = J Psychiatry Neurosci | year = 2001 | month = Jan | volume = 26 | issue = 1 | pages = 44–8 | title = Abrupt discontinuation of psychotropic drugs during pregnancy: fear of teratogenic risk and impact of counselling | author = Einarson A | coauthors = Selby P, Koren G | pmid = 11212593 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1408034&blobtype=pdf | format = PDF ]
* Self harmcite journal | journal = Br J Gen Pract | author = Neale G | coauthors = Smith AJ | year = 2007 | month = May | volume = 57 | issue = 538 | pages = 407–8 | title = Self-harm and suicide associated with benzodiazepine usage | pmid = 17504594 | publisher = pubmed central | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17504594 ]
* Hyperthermiacite journal |journal=Nouv Presse Med |year=1980 |month=Jun |date=28 |volume=9 |issue=28 |pages=1941–5 |title= [Benzodiazepine physical dependence. 6 cases (author's transl)] |author=Bismuth C |coauthors=Le Bellec M, Dally S, Lagier G |pmid=6106922 ]
* Delusions [cite journal |journal=Can J Psychiatry |year=1988 | month=Oct |volume=33 |issue=7 |pages=626–7 |title=Delusional depression following benzodiazepine withdrawal |author=Keshavan MS |coauthors=Moodley P, Eales M, Joyce E, Yeragani VK |pmid=3197017]
* Homicidal ideation [cite journal |author=Risse SC |coauthors= Whitters A, Burke J, Chen S, Scurfield RM, Raskind MA. |title=Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder |journal=The Journal of clinical psychiatry. |volume=51 |issue=5 |pages=206–9 |year=1990 |pmid=2335496]
* Violence [cite journal |author=Citrome L |coauthors= Volavka J. |title=Violent patients in the emergency setting |journal=The Psychiatric clinics of North America. |volume=22 |issue=4 |pages=789–801 |year=1999 |pmid=10623971 |doi=10.1016/S0193-953X(05)70126-X]
*Post Traumatic Stress Disorder
* Psychosis [cite journal |journal=Singapore Med J |year=1989 | month=Feb |volume=30 |issue=1 |pages=72–3 |title=Psychiatric complications of Erimin abuse |author=Peh LH |coauthors=Mahendran R |pmid=2595393]
* Confusion [cite journal |journal=J Clin Psychopharmacol |year=2006 | month=Oct |volume=26 |issue=5 |pages=519–23 |title=Abrupt discontinuation of alprazolam and cognitive style in patients with panic disorder: early effects on mood, performance, and vital signs |author=Uhlenhuth EH |coauthors=Starcevic V, Qualls C, Antal EJ, Matuzas W, Javaid JI, Barnhill J |pmid=16974197 |doi=10.1097/01.jcp.0000236653.85791.60]
* Mania [cite journal |author=Turkington D, Gill P. |title=Mania induced by lorazepam withdrawal: a report of two cases |journal=Journal of affective disorders. |volume=17 |issue=1 |pages=93–5 |month=Jul-Aug |year=1989 |pmid=2525581 |doi=]
* Effects similar to delirium tremens [cite journal | journal = Med J Aust | year = 1972 | month = Aug | date = 19 | volume = 2 | issue = 8 | pages = 450 | title = Delirium tremens following withdrawal of nitrazepam | author = Darcy L | pmid = 5086307 ] [cite journal | journal = Ann Fr Anesth Reanim | year = 1984 | volume = 3 | issue = 5 | pages = 383–4 | title = [Physical dependence on benzodiazepines in traumatology] | author = Berezak A | coauthors = Weber M, Hansmann J, Tulasne PA, Laporte B, Ould Ouali A | pmid = 6149713 ]

Time of appearance and duration

Withdrawal symptoms can occur whilst on a stable dose of benzodiazepines due to the "tolerance withdrawal" phenomenon, where the body experiences "withdrawal effects" and craves increasing doses to feel normal which can lead to dosage escalation, but most often withdrawal symptoms occur during dosage reduction. Onset of the withdrawal syndrome from long half-life benzodiazepines might be delayed for up to 3 weeks, although withdrawal symptoms from short-acting benzodiazepines often presents early usually within 24–48 hours. [cite web |url = http://www.bnf.org/bnf/bnf/54/3139.htm |title = Hypnotics and anxiolytics |accessmonthday = Sep 13 |accessyear = 2007 |author = CSM |year = 2007 |publisher = British National Formulary ]

The acute benzodiazepine withdrawal syndrome generally lasts for about 2 months but clinically significant withdrawal symptoms may persist, although gradually declining, for many months or even several years. The severity and length of the withdrawal syndrome is likely determined by various factors including rate of tapering, length of use of benzodiazepines and dosage size and possibly genetic factors. [cite journal | last = Hood | first = HM | coauthors = Metten P, Crabbe JC, Buck KJ. | year = 2006 | title = Fine mapping of a sedative-hypnotic drug withdrawal locus on mouse chromosome 11 | journal = Genes, brain, and behavior. | volume = 5(1) | pages = 1–10 | pmid = 16436183 | doi = 10.1111/j.1601-183X.2005.00122.x ]

As withdrawal progresses after some weeks or months many individuals begin to experience "windows of normality", where they experience little or no symptoms. These windows can last for hours or days. Over time these windows increase in frequency until withdrawal symptoms completely abate. A theory for this phenomenon is the affinity for GABA of the benzodiazepine receptor is switching from one state to the other as tolerance to the drug is beginning to reverse.

Long term use of benzodiazepines causes cognitive, neurological and intellectual impairments. After one year of abstinence from benzodiazepines cognitive, neurological and intellectual impairments had returned to normal. [cite journal | author =Tönne U | coauthors =Hiltunen AJ, Vikander B, Engelbrektsson K, Bergman H, Bergman I, Leifman H, Borg S | year =1995 |month=May | title =Neuropsychological changes during steady-state drug use, withdrawal and abstinence in primary benzodiazepine-dependent patients | journal =Acta Psychiatr Scand | volume =91 |issue=5 | pages =299–304 | pmid =7639085 | doi =10.1111/j.1600-0447.1995.tb09786.x ]

Reasons for withdrawing

Chronic benzodiazepine users decide to withdraw from benzodiazepines for a variety of reasons including worsening mental and physical health caused by benzodiazepines or increasing cognitive side effects caused by chronic benzodiazepine use.Long term users of benzodiazepines show impairments in visual-spatial ability and sustained attention and posterior cortical cognitive function. [cite journal |author=Golombok S |coauthors=Moodley P, Lader M |title=Cognitive impairment in long-term benzodiazepine users |journal=Psychol Med |volume=18 |issue=2 |pages=365–74 |year=1988 |month=May |pmid=2899898 ] Cognitive impairments including verbal learning and verbal memory, psychomotor, visuo-motor and visuo-conceptual abilities showed some improvements after 6 months post withdrawal from therapeutic doses of benzodiazepines. [cite journal |author=Tata PR |coauthors=Rollings J, Collins M, Pickering A, Jacobson RR |title=Lack of cognitive recovery following withdrawal from long-term benzodiazepine use |journal=Psychol Med |volume=24 |issue=1 |pages=203–13 |year=1994 |month=Feb |pmid=8208885 ]

Chronic long term use of benzodiazepines is associated with an increased risk of impulsive, aggressive and violent behaviour. A study showed that 53% of long term benzodiazepine users showed violent characteristics where as only 5.3% of patients receiving psychotherapy developed violent or aggressive behavioural patterns. [cite journal | author = Mathew VM | coauthors = Dursun SM, Reveley MA | year = 2000 | month = Feb | title = Increased Aggressive, Violent, and Impulsive Behaviour in Patients During Chronic-Prolonged Benzodiazepine Use | journal = Can J Psychiatry | volume = 45 | issue = 1 | pages = 89–90 | publisher = BCNC | pmid =10696503 | url = http://www.bcnc.org.uk/violent.html ] Studies have shown that long term use of benzodiazepines is associated with causing depression as well as a markedly raised suicide risk as well as an overall increased mortality risk. [cite journal | author =Nathan RG | coauthors =Robinson D, Cherek DR, Davison S, Sebastian S, Hack M | year =1985 | month =Jan | title =Long-term benzodiazepine use and depression | journal =Am J Psychiatry | volume =142 | issue =1 | pages =144–5 | publisher =American Journal of Psychiatry | pmid =2857068 | url =http://ajp.psychiatryonline.org/cgi/reprint/142/1/144a ] [cite journal | journal = BMC Psychiatry | year = 2007 | month= Aug |date= 21 |volume= 7 | title= Greater incidence of depression with hypnotic use than with placebo |url =http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17711589 |publisher=pubmed |author =Kripke DF | pmid = 17711589 | doi= 10.1186/1471-244X-7-42 | pages= 42] Daily users of benzodiazepines are also at a higher risk of experiencing psychotic symptomatology such as delusions and hallucinations. [cite journal | author =Tien AY | coauthors =Anthony JC | year =1990 | month =Aug | title =Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences | journal =J Nerv Ment Dis | volume =178 | issue =8 | pages =473–80 | pmid =2380692 ]

A study of 50 patients who attended a benzodiazepine withdrawal clinic found that long term use of benzodiazepines causes a wide range of psychological and physiological disorders. It was found that after several years of chronic benzodiazepine use that a large portion of patients developed various mental and physical health problems including agoraphobia, irritable bowel syndrome, paraesthesiae, increasing anxiety and panic attacks which were not preexisting. The mental health and physical health symptoms induced by long term benzodiazepine use gradually improved significantly over a period of a year following a slow withdrawal. Three of the 50 patients had wrongly been told at one time that they had multiple sclerosis when the symptoms were actually due to chronic benzodiazepine use. Ten of the patients had taken drug overdoses whilst on benzodiazepines despite only two of the patients having had any prior history of depressive symptomatology. After withdrawal no patients took any further overdoses and after 1 year post withdrawal. The cause of the deteriorating mental and physical health in a significant proportion of patients was hypothesised to be caused by increasing tolerance where withdrawal type symptoms emerged despite a stable prescribed doses being taken. [cite journal | author =Professor C Heather Ashton | url =http://www.benzo.org.uk/ashbzoc.htm | year =1987 | title =Benzodiazepine Withdrawal: Outcome in 50 Patients | journal =British Journal of Addiction | volume =82 | pages =655–671 ] Another theory is that chronic benzodiazepine use causes subtle increasing toxicity which in turn leads to increasing psychopathology in long term users of benzodiazepines. [cite journal | author =Michelini S |coauthors=Cassano GB, Frare F, Perugi G | year =1996 | month=Jul | title =Long-term use of benzodiazepines: tolerance, dependence and clinical problems in anxiety and mood disorders | journal =Pharmacopsychiatry | volume =29 |issue=4 | pages =127–34 | pmid =8858711]

The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published paper when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry sponsored trials on their own results showing that use of hypnotics is correlated with depression. The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that "major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia. [cite journal | journal = J Clin Sleep Med | year = 2007 | month = Dec | date = 15 | volume = 3 | issue = 7 | pages = 671–3 | title = Who should sponsor sleep disorders pharmaceutical trials? | author = Kripke DF | pmid = 18198797 | quote = major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks.] Chronic use of benzodiazepines seemed to cause significant immunological disorders in a study of selected outpatients attending a psychopharmacology department. [cite journal | journal = Clin Neuropharmacol | year = 1994 | month = Feb | author = Lechin F | coauthors = van der Dijs B, Vitelli-Flores G, Báez S, Lechin ME, Lechin AE, Orozco B, Rada I, León G, Jiménez V | volume = 17 | issue = 1 | pages = 63–72 | title = Peripheral blood immunological parameters in long-term benzodiazepine users | pmid = 7908607 | doi = 10.1097/00002826-199402000-00007 ] There have been 15 epidemiologic studies which have shown that hypnotic drug use is associated with increased mortality, mainly due to increased cancer deaths in humans. The cancers included cancer of the brain, lung, bowel, breast, and bladder, and other neoplasms. Not only are benzodiazepines associated with an increased risk of cancer, the benzodiazepine receptor agonist Z-drugs also are associated with cancer in humans in these studies. Initially FDA reviewers did not want to approve the Z drugs due to concerns of cancer but ultimately changed their mind and approved the drugs despite the concerns. The data shows that trial subjects receiving hypnotic drugs had an increased the risk of developing cancer.The review author concluded saying; "the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer". [cite journal | last = Kripke | first = Daniel F | year = 2008 | title = Evidence That New Hypnotics Cause Cancer | journal = Department of Psychiatry, UCSD | publisher = University of California | url = http://repositories.cdlib.org/cgi/viewcontent.cgi?article=1002&context=ucsdpsych | format = PDF | quote = the likelihood of cancer causation is sufficiently strong now that physicians and patients should be warned that hypnotics possibly place patients at higher risk for cancer. ]

Benzodiazepine withdrawal management

See also Benzodiazepine half life and equivalency table

The success rate of a slow withdrawal schedule is approximately 65%. Studies have shown that psychiatric patients have a similar success rate of staying off benzodiazepines after a slow withdrawal schedule at 2 year followup post withdrawal. [cite journal |author=Kan CC |coauthors=Mickers FC, Barnhoorn D |title= [Short- and long-term results of a systematic benzodiazepine discontinuation programme for psychiatric patients] |journal=Tijdschr Psychiatr |volume=48 |issue=9 |pmid=17007474 |year =2006 |pages=683–93 ] The slower the withdrawal rate the less intense the withdrawal symptoms and there is strong anecdotal evidence that slower withdrawal rates decrease the risk of developing a severe protracted benzodiazepine withdrawal syndrome. The rate of withdrawal preferably utilising either diazepam or chlordiazepoxide for their long half lifes and low potency dose forms, is best carried out according to the withdrawing patient's body response to dose cuts. The British National Formulary, a medical guidance book which is issued to all British doctors, states that it is better to withdraw too slowly rather than too quickly from benzodiazepines. [cite web|url= http://www.bnf.org/bnf/bnf/55/3139.htm|title= Hypnotics and anxiolytics|accessdaymonth= 5 Sep|accessyear= 2008|author= British National Formulary|authorlink= British National Formulary|coauthors= Committee on Safety of Medicines|publisher= BNF.org]

People withdrawing from benzodiazepines should be careful that they do not supplement their benzodiazepines for drugs which work through the same or similar GABA mechanism including alcohol, barbiturates and the nonbenzodiazepine Z drugs otherwise they may keep the dependency going.

Fluoroquinolone antibiotics have been noted by Professor Heather Ashton and confirmed in a study as often causing serious complications in patients taking or undergoing withdrawal from benzodiazepines. This is probably the result of the GABA antagonistic effect of fluoroquinolones. Fluoroquinolones have also been found to competitively displace benzodiazepines from benzodiazepine receptors which can precipitate acute withdrawal symptoms in benzodiazepine dependent subjects. A study reported higher than usual CNS toxicity from fluoroquinolones in subjects who were dependent on or in withdrawal from benzodiazepines. Of the general public 1 - 4% of the public will experience CNS toxicity from fluoroquinolones which may be severe. The incidence of severe CNS toxicity occurs significantly more frequently in the benzodiazepine dependent population. The CNS adverse reactions from fluoroquinolones were similar to those seen in benzodiazepine withdrawal and persisted for weeks or months before subsiding. The symptoms included depression, anxiety, psychosis, paranoia, severe insomnia, parathesia, tinnitus, hypersensitivity to light and sound, tremors, status epilepticus, suicidal thoughts and suicide attempt. The study confirmed that fluoroquinolone CNS toxicity can be serious, occurs more frequently in benzodiazepine dependent subjects and concluded that fluoroquinolone antibiotics should be contraindicated in patients who are dependent on or in benzodiazepine withdrawal. [cite journal |author=McConnell JG |title= Benzodiazepine tolerance, dependency, and withdrawal syndromes and interactions with fluoroquinolone antimicrobials |journal=British Journal of General Practice | publisher = Royal College of General Practitioners |volume=58 |issue=550 |month=May |year =2008 |pages=365–366 |doi=10.3399/bjgp08X280317 |url=http://www.ingentaconnect.com/content/rcgp/bjgp/2008/00000058/00000550/art00020 ] [cite journal |year=1990 |month=jul |volume=58 |issue=1 |pages=63–70 |author=Unseld E |coauthors= Ziegler G, Gemeinhardt A, Janssen U, Klotz U |title= Possible interaction of fluoroquinolones with the benzodiazepine-GABAA-receptor complex |journal=Br J Clin Pharmacol |url=http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1368276&blobtype=pdf |pmid=2167717 ]

Antipsychotics should be avoided during benzodiazepine withdrawal as they tend to aggravate withdrawal symptoms, including convulsions. [cite web |url = http://www.bnf.org/bnf/bnf/54/3139.htm |title = Hypnotics and anxiolytics |accessmonthday = Sep 17 |accessyear = 2007 |author = Committee on Safety of Medicines |year = 2007 |publisher = British National Formulary] [cite journal |author=Tagashira E |coauthors=Hiramori T, Urano T, Nakao K, Yanaura S. |title=Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents |journal=Jpn J Pharmacol. |volume=31 |issue=5 |pages=689–99 |month=Oct |year=1981 |pmid=6118452 |doi=10.1254/jjp.31.689 ] The addition of an SSRI antidepressant has been found to have little value in the treatment of benzodiazepine withdrawal. [cite journal |year=2001 |month=Apr |volume=178 |pages=317–24 |author=Zitman FG |coauthors= Couvée JE |title= Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper-off: report on behalf of the Dutch Chronic Benzodiazepine Working Group |url= |pmid=11282810 |journal=Br J Psychiatry |doi=10.1192/bjp.178.4.317 ]

Once the benzodiazepine addicted or physically dependent individual has successfully withdrawn from benzodiazepines they should avoid taking even occasionally benzodiazepines or cross tolerant drugs such as alcohol, barbiturates or the nonbenzodiazepines for between four months and two years, depending on personal biochemisty. This is because tolerance to benzodiazepines has been demonstrated to be still present in patients who have discontinued benzodiazepines between four months and two years post withdrawal. In these patients even once off low dose re-exposures to benzodiazepines typically resulted in a reactivation of the tolerance and benzodiazepine withdrawal syndrome. [cite journal |year=1988 |month= |volume=13 |pages=1–55 |author=Higgitt A |coauthors=Fonagy P, Lader M |title=The natural history of tolerance to the benzodiazepines |pmid=2908516 |journal=Psychol Med Monogr Suppl ]

Detoxification of a benzodiazepine dependent individual is often carried out using an equivalent dose of either diazepam or chlordiazepoxide to the benzodiazepine the individual is dependent on and by reducing in steps of 10% every 2–4 weeks depending on the severity of the dependency and the patient's response to reductions. However, if withdrawal is carried out slow enough and preferably using an equivalent dose of diazepam or chlordiazepoxide to withdraw, many benzodiazepine dependent patients find that they experience little or sometimes no withdrawal when it comes time to come off the last 0.5 mg dose of diazepam or 5 mg dose of chlordiazepoxide. Those who have withdrawn slow enough but still experience withdrawal effects typically find that their withdrawal symptoms have largely disappeared after a few months.

It is strongly recommended that during benzodiazepine withdrawal that the drug used is diazepam (Valium) or chlordiazepoxide (Librium) as they has a longer half-life than most other benzodiazepines such as Lorazepam (Ativan) and hence a smoother withdrawal. [cite web | url = http://www.bcnc.org.uk/whyvalium.html | title = The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam | author = DR JG McConnell | date = 6 | year = 2007 | month = May | publisher = BCNC ] It is virtually impossible to withdraw successfully if the addiction is to a short to intermediate half-life hypnotic benzodiazepine such as Temazepam (Normison), the toll on the body is too high and debilitating. [cite journal |author=Strang J et al |title=In Benzodiazepine Dependence |journal=Oxford Medical Publications |volume=23 |pages=128–42 |month=Jul |year=1993] It is also critical that whilst the early and mid part of withdrawal should be managed with a 1 mg (for diazepam) or 5 mg (for chlordiazepoxide) reduction every 2 weeks, the reduction down to 5 mg (for diazepam) or 12.5 mg (for chlordiazepoxide) daily is a key milestone. From 5 mg down to 0 mg (for diazepam) or 12.5 mg to 0 mg (for chlordiazepoxide) a taper of 0.5mg (for diazepam) or 1.25 mg (for chlordiazepoxide) reduction every three weeks makes this much more tolerable on the mind and body. Usually, for most people, once off the drug, a sense of relief and well-being can be felt after 2–3 months of total abstinence.

It is very important to use the correct benzodiazepine equivalencies when switching benzodiazepines either therapeutically or in the management of withdrawal. This importance was illustrated in a case reported in the medical literature of a man who had been taking doses of lorazepam and alprazolam equivalent of 60 mg of diazepam. He was then switched from the lorazepam and alprazolam to only 7 mg of diazepam per day. Within 36 hours the patient developed somatic symptoms and became convinced that he had an underlying pathology and impulsively attempted suicide by stabbing himself in the abdomen causing himself serious injury requiring emergency surgery. His symptoms and suicide attempt were diagnosed by his GP and psychiatrist as benzodiazepine withdrawal. The patient again tried to withdraw from benzodiazepines but again attempted suicide by inflicting serious stab wounds to his neck and chest which resulted in admittance to a psychiatric unit. The author warned that self harm can be a feature of benzodiazepine withdrawal.cite journal | journal = Br J Gen Pract | author = Neale G | coauthors = Smith AJ | year = 2007 | month = May | volume = 57 | issue = 538 | pages = 407–8 | title = Self-harm and suicide associated with benzodiazepine usage | pmid = 17504594 | publisher = pubmed central | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17504594 ]

High dose withdrawal

Abrupt withdrawal from very high doses can cause severe withdrawal effects. Withdrawal from high dose abuse of nitrazepam have caused severe hypoperfusion of the whole brain with diffuse slow activity on EEG. After withdrawal, abnormalities in hypofrontal brain wave patterns persist beyond the withdrawal syndrome which suggested organic brain damage occurs from chronic high dose abuse of benzodiazepines.cite journal |author=Kitabayashi Y, Ueda H, Narumoto J, "et al" |title=Chronic high-dose nitrazepam dependence 123I-IMP SPECT and EEG studies |journal=Addict Biol |volume=6 |issue=3 |pages=257–261 |year=2001 |pmid=11900604 |doi=10.1080/13556210120056507] High dose abusers of benzodiazepines have enlarged cerebrospinal fluid spaces with associated brain shrinkage. [cite journal |author=Schmauss C |coauthors=Krieg JC |title=Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers |journal=Psychol Med |volume=17 |issue=4 |pages=869–73 |year=1987 |month=Nov |pmid=2893406 ]
Neuropsychological function can be permanently affected by abuse of benzodiazepines with brain damage similar to alcoholic brain damage, as was shown in a 4– to 6-year follow-up study of benzodiazepine abusers by Borg and others of the Karolinska Institute. The CT scan abnormalities showed dilatation of the ventricular system. However, unlike alcoholics, hypnotic abusers showed no evidence of widened cortical sulci. The study concluded that, when cerebral disorder is diagnosed in hypnotic benzodiazepine abusers, it is often permanent. [cite journal |author=Borg S |coauthors= Bergman H, Engelbrektson K, Vikander B. |title=Dependence on sedative-hypnotics: neuropsychological impairment, field dependence and clinical course in a 5-year follow-up study |journal=British journal of addiction. |volume=84 |issue=5 |pages=547–53 |year=1989 |pmid=2743035 |doi=10.1111/j.1360-0443.1989.tb00612.x ] An earlier study by Borg et al. found evidence of cerebral disorder in those that exclusively abused benzodiazepines, suggesting that cerebral disorder was not the result of other substances of abuse. [cite journal |author=Borg S |coauthors= Bergman H, Holm L. |title=Neuropsychological impairment and exclusive abuse of sedatives or hypnotics |journal=The American journal of psychiatry. |volume=137 |issue=2 |pages=215–7 |year=1980 |month =Feb |url=http://www.ajp.psychiatryonline.org/cgi/content/abstract/137/2/215 |pmid=7352578 ]

Variations

Some people experience little or no withdrawal when stopping long term benzodiazepine usage. It is not known for sure why there is such a variation between patients but recent research in animals suggests that withdrawal from sedative hypnotic drugs may be influenced by a genetic component. [http://www.bcnc.org.uk/gene.html] As withdrawal progresses patients often find that their physical and mental health improves with improved mood and improved cognition.

Complications

Over-rapid withdrawal and lack of explanation and failure to reassure individuals that what they are experiencing is withdrawal symptoms and is temporary have led some people to experience increased panic and fears that they are going mad, with some people developing Post Traumatic Stress Disorder as a result. A slow withdrawal regime coupled with reassurance seems to improve the outcome for individuals undergoing benzodiazepine withdrawal.

Protracted withdrawal

Benzodiazepine dependence is a potentially clinically serious condition and its withdrawal syndrome is complex and often protracted in time course. [cite journal | author = O'Connor RD | year = 1993 | month = | title = Benzodiazepine dependence--a treatment perspective and an advocacy for control | journal = NIDA Res Monogr | volume = 131 | pages = 266–9 | pmid = 8105385 ]

Protracted withdrawal symptoms refers to symptoms persisting for a protracted time, perhaps year or more. Patients who experience protracted withdrawal from benzodiazepines, which more commonly occurs from over-rapid withdrawal, can be reassured that the evidence shows that symptoms do continue to fade and return to normal over a period of many months or several years. A figure of 10-15% of patients withdrawing from benzodiazepines may experience a protracted withdrawal syndrome.cite web| author= Professor Heather Ashton| year= 2004| url= http://www.bcnc.org.uk/protracted.html| title= Protracted Withdrawal Symptoms From Benzodiazepines | publisher= Comprehensive Handbook of Drug & Alcohol Addiction] There is strong anecdotal evidence that a slow-withdrawal rate significantly reduces the risk of a protracted and/or severe withdrawal state. About 10–15% of people who discontinue benzodiazepines develop protracted withdrawal syndrome. There is no known cure for protracted benzodiazepine withdrawal syndrome except time. [cite web |url= http://www.bcnc.org.uk/protracted.html |title= Protracted withdrawal symptoms from benzodiazepines |author= Professor C Heather Ashton |year= 2004] The post withdrawal syndrome may linger for many months in 10-15% of people and for a smaller number of unfortunate patients for several years.Studies following people up beyond the initial acute withdrawal stage have shown that for many patients symptoms continue to improve the longer they stay off the drug, often to the point where they can eventually resume their normal lives even after years of incapacity imposed by chronic benzodiazepines.The causes of persisting benzodiazepine withdrawal symptoms are a combination of pharmacological factors such as persisting drug induced receptor changes, psychological factors both caused by the drug and separate from the drug and possibly in some cases, particularly high dose users structural brain damage or structural neuronal damage. [cite journal | journal = Psychiatric Annals | year = 1995 | month = Mar | volume = 25 | issue = 3 | pages = 174–179 | title = Protracted Withdrawal From Benzodiazepines: The Post-Withdrawal Syndrome | author = Ashton CH | publisher = benzo.org.uk | url = http://www.benzo.org.uk/pha-1.htm ] [cite journal | journal=J Subst Abuse Treat | year =1991 | volume=8 | issue=1-2 | pages=19–28 | title=Protracted withdrawal syndromes from benzodiazepines | author=Ashton H |pmid=1675688 |url=http://www.benzo.org.uk/ashpws.htm |publisher=benzo.org.uk | doi=10.1016/0740-5472(91)90023-4]

Disturbances in mental function can persist for several months or sometimes longer. Psychotic depression persisting for more than a year following benzodiazepine withdrawal has been documented in the medical literature. The patient had no prior psychiatric history. The symptoms reported in the patient included, major depressive disorder with psychotic features, including persistent depressed mood, poor concentration, decreased appetite, insomnia, anhedonia, anergia and psychomotor retardation. The patient also had paranoid ideation believing she was being poisoned and persecuted by co-employees, and sensorary hallucinations. Symptoms developed after abrupt withdrawal of chlordiazepoxide and persisted for 14 months. Various psychiatric medications were trialed which were unsuccessful in alleviating the symptomatology. Symptoms were completely relieved by recommencing chlordiazepoxide for irritable bowel syndrome 14 months later. [cite journal | journal = Psychosomatics | year = 1997 | month = Mar-Apr | volume = 38 | issue = 2 | pages = 160–1 | title = Protracted benzodiazepine withdrawal syndrome mimicking psychotic depression | author = Modell JG | pmid = 9063050 | publisher = Psychiatry Online | url = http://psy.psychiatryonline.org/cgi/reprint/38/2/160.pdf | format = PDF ] Sensorary withdrawal related disturbances which can be acute or protracted in duration and are among the clinical features of the benzodiazepine withdrawal syndrome. Protracted tinnitus has been found to be a complication of discontinuation of benzodiazepines with tinnitus persisting for many months or up to a year or more after discontinuation of therapeutic doses of benzodiazepines. Appearance of the tinnitus occurs during dose reduction or discontinuation of benzodiazepines and is alleviated by recommencement of benzodiazepines. [cite journal | journal = J Clin Psychopharmacol | year = 1988 | month = Oct | volume = 8 | issue = 5 | pages = 359–62 | title = Protracted Tinnitus after Discontinuation of Long-Term Therapeutic Use of Benzodiazepines | author = Busto U | coauthors = Fornazzari L, Naranjo CA | pmid = 2903182 | url = http://www.benzo.org.uk/busto.htm | doi = 10.1097/00004714-198810000-00010 ] cite journal | journal = BMJ | year = 1991 | month = Jun | date = 15 | volume = 302 | issue = 6790 | pages = 1465 | title = Benzodiazepines and tinnitus | author = Beeley L | pmid = 2070121 | url = http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1670117&blobtype=pdf | format = PDF ]

A meta-analysis found that the literature shows that cognitive impairments due to benzodiazepines use shows improvements after 6 months after withdrawal but the remaining cognitive impairments may be permanent or may require more than 6 months to return to normal. [cite journal| journal =Arch Clin Neuropsychol | year =2004| month =Apr| volume =19| issue =3| pages =437–54| title =Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis| author =Barker MJ| coauthors =Greenwood KM, Jackson M, Crowe SF| pmid =15033227| doi =10.1016/S0887-6177(03)00096-9]

Neuropsychological testing of a group of patients with persistent benzodiazepine withdrawal symptoms found that psychophysiological markers differed from normal anxiety markers. The study of the group of patients concluded that protracted withdrawal symptoms were a genuine iatrogenic condition caused by the long term prescription of benzodiazepines. [cite journal| journal =Acta Psychiatr Scand.| year =1990| month =Aug| volume =82| issue =2| pages =165–8| title =The prolonged benzodiazepine withdrawal syndrome: anxiety or hysteria?| author =Higgitt A| coauthors =Fonagy P, Toone B, Shine P| pmid =1978465| doi =10.1111/j.1600-0447.1990.tb01375.x]

Hoffmann–La Roche pharmaceutical company, the manufacturer of Klonopin (clonazepam), in a 2007 product information publication, acknowledges the existence of protracted benzodiazepine withdrawal syndromes and recommends that its product flumazenil is not used to treat protracted benzodiazepine withdrawal syndromes. [cite web |url= http://www.rocheusa.com/products/romazicon/pi.pdf |title= Romazicon |author= Roche USA |year= 2007 |month= Oct |format= PDF |publisher= Roche Pharmaceuticals USA]

Examples

Some common protracted withdrawal symptoms include: cognitive deficits, gastrointestinal complaints, insomnia, tinnitus, paraesthesiae (tingling and numbness), pain (usually in limbs and extremities), muscle pain, weakness, tension, painful tremor, shaking attacks, jerks, and blepharospasm.cite web| author= Professor Heather Ashton| year= 2004| url= http://www.bcnc.org.uk/protracted.html| title= Protracted Withdrawal Symptoms From Benzodiazepines | publisher= Comprehensive Handbook of Drug & Alcohol Addiction]

Effect of flumazenil

A study into the effects of the benzodiazepine receptor antagonist, flumazenil, on benzodiazepine withdrawal symptoms persisting after withdrawal was carried out by Lader and Morton. Study subjects had been benzodiazepine-free for between one month and five years, but all reported persisting withdrawal effects to varying degrees. Persistent symptoms included clouded thinking, tiredness, muscular symptoms such as neck tension, cramps and shaking and the characteristic perceptual symptoms of benzodiazepine withdrawal, namely, pins and needles, burning skin, pain and subjective sensations of bodily distortion. Therapy with 0.2–2 mg of flumazenil intravenously was found to decrease these symptoms in a placebo controlled study. This is of interest as benzodiazepine receptor antagonists are neutral and have no clinical effects. The author of the study suggested that the most likely explanation is that past benzodiazepine use and subsequent tolerance had locked the conformation of the GABA-BZD receptor complex into an inverse agonist conformation, and that the antagonist flumazenil resets benzodiazepine receptors to their original sensitivity. Flumazenil was found in this study to be a successful treatment for protracted benzodiazepine withdrawal syndrome, but it was noted that further research is required. [cite web| author= Professor Malcolm Lader| year= 1992| url= http://www.bcnc.org.uk/flumazenil.html| title= A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal| publisher= Journal of Psychopharmacology]

Cognitive behavioral therapy

Nitrazepam, temazepam and zopiclone are the most frequently prescribed hypnotics in the United Kingdom. Hypnotic drugs are of poor value for the management of chronic insomnia. Hypnotic drug consumption has been shown to reduce work performance, increase absenteeism, increase road traffic accidents, increased morbidity, increase mortality and is associated with an increased incidence of deliberate self harm. In the elderly, increases in falls and fractures associated with sedative hypnotic drug use has been found. It is widely accepted that hypnotic drug usage beyond 4 weeks is undesirable for all age groups of patients. Many continuous hypnotic users exhibit disturbed sleep as a consequence of tolerance but experience worsening rebound or withdrawal insomnia when the dose is reduced too quickly which compounds the problem of chronic hypnotic drug use. Cognitive behavioural therapy has been found to be more effective for the long term management of insomnia than sedative hypnotic drugs. No formal withdrawal programs for benzodiazepines exists with local providers in the UK. Meta-analysis of published data on psychological treatments for insomnia show a success rate between 70 and 80%. A large scale trial utilising cognitive behavioural therapy in chronic users of sedative hypnotics including nitrazepam, temazepam and zopiclone found CBT to be a significantly more effective long term treatment for chronic insomnia than sedative hypnotic drugs. Persisting improvements in sleep quality, sleep onset latency, increased total sleep, improvements in sleep efficiency, significant improvements in vitality, physical and mental health at 3, 6 and 12 month follow up was found in those receiving cognitive behavioural therapy. A marked reduction in total sedative hypnotic drug use was found in those receiving CBT, with 33% reporting zero hypnotic drug use. Age has been found not to be a barrier to successful outcome of CBT. It was concluded that CBT for the management of chronic insomnia was flexible, practical and a cost effective treatment and it was also concluded that CBT leads to a reduction of benzodiazepine drug intake in a significant number of patients. [cite journal | author = Morgan K | coauthors = Dixon S, Mathers N, Thompson J, Tomeny M. | year = 2004 | month = Feb | title = Psychological treatment for insomnia in the regulation of long-term hypnotic drug use | journal = Health Technol Assess. | volume = 8 | issue = 8 | pages = 1–68 | publisher = National Institute for Health Research | pmid = 14960254 | url = http://www.hta.ac.uk/fullmono/mon808.pdf | format = PDF ]

Detox Controversy

In some instances, a "Detox" or other inpatient facility will take a patient off a benzodiazepine "cold turkey" — replacing it with a short taper of Phenobarbital (a barbiturate) to prevent seizures. This method of coming off a benzodiazepine is highly controversial and often called "barbaric." Most Physicians and medical authorities agree that in the majority of cases a slow taper is preferred to a rapid taper or "cold turkey" withdrawal from a benzodiazepine.

However, more recent research is showing promise with the use of flumazenil in the management of benzodiazepine detoxification. Flumazenil has been found to stimulate the reversal of tolerance and the normalisation of receptor function. Flumazenil stimulates the upregulation and reverses the uncoupling of benzodiazepine receptors to the GABA receptor thereby reversing tolerance and reducing withdrawal symptoms and relapse rates. [cite journal |journal=Addict Biol |year=2002 |month=Oct |volume=7 |issue=4 |pages=385–95 |title=Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study |author=Gerra G | coauthors = Zaimovic A, Giusti F, Moi G, Brewer C |pmid=14578014 |doi=10.1080/1355621021000005973 ]

ee also

* Alcohol withdrawal syndrome
* Benzodiazepine equivalence
* Benzodiazepine
* Post Acute Withdrawal Syndrome
* SSRI discontinuation syndrome

References

External links

* [http://www.benzo.org.uk/manual/ Benzodiazepines: How they work and how to withdraw by Professor Heather Ashton]
*DMOZ|Health/Mental_Health/Disorders/Substance_Related/Support_Groups/


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